Background: Gradual discontinuation of lithium may reduce high risk of early morbidity in bipolar disorder patients discontinuing successful long-term maintenance on lithium, but previous small samples have limited analyses of subgroups.

Results: After gradual versus rapid discontinuation, the overall median time to recurrence ± SE differed by 5.0-fold (20.0 ± 5.8 vs. 4.0 ± 0.7 months; p < .0001). After rapid discontinuation, the median time in remission was 2.3 times shorter than the mean cycling interval before lithium (6.3 vs. 14.6 months; p < .0001). The proportion of subjects falling ill/month (recurrence rate) was much higher in the first year after rapid discontinuation (6.5% vs. 2.3%), but similar thereafter (0.4% vs. 0.6%); patients remained stable for 3 years when off lithium treatment 20 times more frequently after gradual than rapid discontinuation (37% vs. 1.8%; p < .0001). Ratios of median survival times after gradual/rapid lithium discontinuation were similar for a first recurrence of mania and depression (4.4- vs. 3.4-fold), insignificantly higher (34%) with rapid or continuous cycling before lithium, and greater in Type II than Type I disorder (9.8- vs. 4.0-fold). The polarity of first off-lithium and first lifetime episodes matched in 70% of cases.

Conclusion: These pooled results strengthen the concept of a pharmacodynamic stress factor in early relapse after stopping lithium maintenance and support the conclusion that early recurrence risk can be minimized by discontinuing maintenance treatment gradually in both Type I and II bipolar disorders.​